Chemical processes



. Patented Oct. 9, 1945 .UNITED STATES PATENT OFFICE CHEMICAL PROCESSES .Hans It. Rosenberg, Wilmington, Del., assignor to E. I. du Pont de Nemours a Company, Wilmington, Del., a corporation of Delaware No Drawing. Application October 17, 1941, Serial No. 415.490

3 Claims.

This invention relates to the production of provitamin D which can be activated to vitamins D. More particularly it relates to the production of 7-dehydro sterols from the oxidation products of water insoluble sterol compounds. In one of its aspects it relates to the production of 7-113- droxy sterols in a single step oxidation from sterols.

This invention has for an object the provision of a. new method of obtaining 7-dehydro sterols. A further object is to provide a method for producing 7-dehydro' sterols from .oxidized sterol compounds. A further objectis to provide a new method of obtaining '7-dehydro sterols from water insoluble esters and 'ethers of sterols. Still further objects will be apparent fromthe following description of the invention.

metal salt of an organic carboxylic acid, an oxide of a polyvalent metal or an acid derived from a polyvalent metal, the metals of which are at their higher valences, whereby an appreciable amount of 7-hydroxy sterol compounds are formed. When sterol esters are used as reactants in the oxidation and when polyvalent metal salts of an organic carboxylic acid as described is used as an oxidizing agent, 'I-hydroxy sterol diesters are formed. The entire oxidation mixture may then be subjected to a selective acid splitting rei action to form 'l-ciehydro esters which may be subsequently saponifled to form 7-dehydro compounds.

The invention will be further illustrated but is not intended to be limited by the following ex- Sterol compounds have previously been sub jected to various types of oxidation agents and under various conditions and a wide variety of products have been obtained thereby. It was not known, however, prior to this invention that (a) an oxidation mixture obtainable by oxidizing sterols could be converted to 'hdehydro compounds by an economical procedure and (b) an appreciable amount of '7-hydroxy sterols could be obtained by a simple oxidation of sterols.

-It has now been found that water insoluble sterol compounds including sterols and their 4 easily hydrolyzable esters and ethers when oxidized at moderate temperatures under mild conditions, form an oxidation mixture from which 7-hydroxy sterol compounds can be recovered and converted into 7-dehydro sterols.

In a more limited sense, sterol compounds of the general formula:

wherein X stands for a hydroxyl group or a water insoluble group which can be converted into a hydroxyl group by hydrolysis and R stands for an aliphatic hydrocarbon radical, are treated under mild conditions vwith an oxidizing agent and the resultin products converted into 7-de-- hydro-sterol compounds.

In one important aspect of the invention, water insoluble sterol compounds of the above formula are oxidized in an organic liquid medium at a temperature below 100 C. with a polyvalent amples wherein the parts stated are parts by weightunless otherwise indicated.

E'lrample 1' One part of cholesterol acetate is dissolved in 20 parts glacial acetic acid and 1.12 parts of lead tetra-acetate are added while vigorously stirring and keeping the temperature at C. After several hours the oxidation is completed and the material is poured on ice and water and extracted with ether. The ether solution is washed neutral and added to a solution of 0.5 part of potassium hydroxide in 10 parts of ethyl alcohol. The ether is distilled oil and the remaining alcoholic liquid is refluxed for 1 hour. After cooling, the saponi-' 7-dehydro-cholesterol-benzoate crystallizes out.-

It is filtered off and saponified with 5% ethyl alcoholic caustic potash by heating the solution to boiling to yield 7-dehydro-cholesterol.

Example II One part of cholesterol acetate is dissolved in 10 parts of glacial acetic acid and 1.8 parts of lead tetra-acetate are added. The mixture is kept at C. over a period of several hours at the end of which the material is diluted with water and extracted with ether. The ether solution is washed neutral and saponified with potassium One part of cholesterol benzoate is dissolved in 1 part of dry benzene and 2 parts of lead tetrabenzoate are added while stirring. The mixture is refluxed for 2 hours at the end of which '7- hydroxy-cholesterol-dibenzoate is formed which is washed with water, taken up in methanol, crystallized from an ether-methanol solution and isolated in the usual manner. From the dibenzoate, benzoic acid is selectively removed by refluxing with dimethylaniline for 2 hours. The

'I-dehydro-cholesterol-benzoate obtained is converted into 7-dehydro-cholestero1 by sa'ponifying the ester with an alcoholic potassium hydroxide solution after themanner described in Example I.

Example IV- One part of sitosterol is dissolved in acetic acid and 2 parts of mercuric acetate are added. The material is allowed to remain at room temperature over the period of several weeks during which time mercurous acetate crystallizes out.' This material is .iiltered oil. and the resulting, solution is poured in water and extracted with ether. The

residue from the purified ether solutionis saponi fled in the manner described in Example I and 7-hydroxy sitosterol recovered. 'l-hydroxy-sitosterol-dibenzoate is obtained by reacting the 7- hydroxy sitosterol witha benzolating agent, e. g. benzoyl chloride in the presence of pyridine. It is converted into. '1-dehydro-sitosterol-benzoate by heating under reduced pressure to 200 C. for two hours. The reaction product upon hydrolysis yields 7-dehydro- -sitosterol.

Example V Five parts of cholesterol acetate (M. P. 111-113 C.) are dissolved in 50 parts of glacial acetic acid at a temperature of about 55 C., while agitating. Then a chromic acid solution of 2 parts of chromic acid in 12 parts of 80% acetic acid is run into the cholesterol acetate solution over a period of about 4 hours at such a speed that the inner temperature remains at 55 C. After all the chromic acid solution has been added, heating is continued for a further 2-hour period at 55 C. Acetic acid is then removed by vacuum distillation at a pressure of about 10-,20 mm. and the residue is heated with 15 parts of methanol for several hours. Upon cooling, a by-product material crystallizes out. The 7-hydroxy-cholesterol-compound is present in the mother liquors which are saponifled by adding 1 part of potassium hydroxide in 5 parts of alcohol and refluxing for 1 hour. The 7-hydroxy-cholesterol present is extracted with ether and is converted into '7-dehydro-cholesterol according to the manner set forth in Example 1.

Example VI while vigorously stirring. After heating for 10 hours, the excess pyridine is removed by distillation under vacuum and the residue is extracted with ether. The ether solution is then washed with dilute alkali solutions and with dilute acid solutions and finally with water. The material is then saponifled with dilute alcoholic caustic soda and yields 7-hydroxy-cholesterol which can be extracted with ether and crystallized from methanol.

Example VII One part of cholesterol is dissolved in 10 parts of dioxane and 0.35 parts of p-benzoquinone are added. After standing over a period of several days, the dioxane is removed by distillation under reduced pressure until about 1 part of dioxane is left. The residue contains a 7-hydroxy-cholesterol compound which can be extracted in ether and reacted to form esters.

Example VIII Two parts of cholesterol are dissolved in 20 parts of carbon tetrachloride and 2 parts of benzoyl peroxide are added. The mixture is refluxed for 3 hours. After the completion of this reaction, the solution is extracted with an aqueous solution of sodium hydroxide. The carbon tetrachloride is then distilled off and the residual sterol compound is saponifled with alcoholic potassium hydroxide. The 7-hydroxy-cholesterol is isolated from the saponification mass by extraction with an organic solvent and is benzoylated to yield 7 hydroxy-cholesterol-dibenzoate. The latter is dissolved in dioxane and heated in a sealed system to 200" C. for two hours. After saponiiicatio'n of the reaction product with alcoholic potash, -7-dehydro-cholesterol is obtained.

Example IX Cholesterol acetate is dissolved in acetic acid and while stirring vigorously at a temperature of C. manganese dioxide is added. The mixture is stirred .continuously for several hours at the end of which the 'l-hydroxy compound is worked up as set forth in previous examples and is converted into 7-dehydro-cholesterol by heating with benzoic anhydride for one hour to 190 C.

In place of the specific sterol compounds listed in the above examples, there may be substituted a number. of other water insoluble sterol compounds. The sterol compounds of the respective examples can be interchanged and reacted with the respective oxidizing agents in any desired manner. Thus cholesterol, stigmasterol, sitosterol and their water insoluble or neutral esters such as acetates, propionates, benzoates. cholorbenzoates, chlorides and ethers, e. g. the trlphenyl carbinol ether, are useful in the above described procedures.

The invention is, of course, not limited to the above described oxidizing agents, on the contrary, other equivalent agents may be used under similar mild conditions. The agents of the respective examples may be interchanged in any desired manner. The oxidation. may be carried out over a fair range of temperature conditions. It is generally advantageous, however, to use temperatures from 50 to 0. especially if an acid medium is used as a solvent. In general, the oxidizing agent is added in an amount at least equal to that theoretically necessary to introduce one oxygen atom into the sterol nuclei. An excess of at least double the theoretical is preferred however.

assaoss 3 The oxidation of the sterol compounds can be carried out in the presence of various organic solvents or diluents for the sterol type compounds. The solvents chosen should not have a deleterious effect on the sterol type compounds however. In addition to the solvents mentioned in the examples, there can be substituted toluene, xylene; chlorinated hydrocarbons e. g. chloroform, carbon tetrachloride, methylene chloride, ethylene chloride, etc.; ethers such as dioxane, and similar solvents.

The 7-hydroxy sterol compounds can be recovered from the oxidation mixture by utilizing various other organic solvents in place of those specified in the examples including those mentioned in the preceding paragraph. Ethers, such as dimethyl ether and diethyl ether are also useful solvents for the extraction procedures.

. The acidic impurities are preferably removed before extraction by washing and/or treatment compounds and/or other agents as described in Rosenberg and Parsons application, Ser. No. 283,294, filed July l7, 1939, and in other manners.

This invention provides a method of obtaining 7-dehydro sterol compounds which are provitamins D from water insoluble sterol compounds in a simple manner. It provides a novel method of obtaining 7-hydroxy sterol compounds in a simple manner involving a few procedural steps. It enables 7-hydroxy sterol compounds to be prepared from sterols in a simple manner.

As many apparently widely difierent embodiments of this invention may be made without departing from the spirit and scope thereof, it is to be understood that the invention is not to be limited by the embodiments herein except as defined by the appended claims.

with alkaline liquids, such as dilut aqueous or alcoholic solutions of caustic alkalis. However, they may be removed after extraction by treating the extract with alkali solutions and washing. In place of the specific quinone mentioned in the examples other quinone oxidizing agents may be substituted. Among the suitable ones are alizarin-quinone and 2,3-dichloro 1,4,9,10-anthracene diquinone, ortho benzoquinone, tetrachloro-p-quinone and diphenoquinone.

The esterificationof the 7-hydroxy group may be carried out in various manners, for instance,

by means 0! monocarboxylic acids or their acid halides, or acid anhydrides such as benzoyl chloride, acetyl chloride, acetic anhydride, nitrobenzoic, m-dinitrobenzoic, chlorobenzoic, toluic, phenylactic, cinnamic, formic, propionic, butyric and Valerie, etc. acids. The esterification, especially when acyl halides are used, is advantageously carried out in the presence of an organic base. e. g. pyridine, piperidine, piperazine, aniline, dimethyl aniline, dietlrvl-a-naphthyl amine, dimethyl stearyl amine, morpholine, triethylamine, allrylolamines, etc.

The conversion of the esterified 7-hydroxy compounds can be carried out in a number of ways, for example, they may be subjected to thermal decomposition by heating to elevated temperatures e. g. 150 to 200 C. at reduced pressures, after the manner of U. S. P. 2,098,984. They may be converted to 7-dehydro sterol compounds with the aid or organic nitrogen containing bases after the manner of U. S. P. 2,209,934 or with the aid of oxonlum salt forming 40 .produce I claim:

1. A process for producing 'I-dehydro-cholesterol which comprises dissolving in an organic solvent a member selected from the class consisting of cholesterol and its carboxylic acid esters,,heating'said solution in the presence of an oxidizing agent, separating from the reaction mixture the so -produced 7-hydroxy cholesterol, converting said compound to 7-hydroxy-cholesterol dibenzoate, thermally decomposing said diester to produce 7-dehydro-cholesterol-benzoate, and saponiiying said product to produce 7-dehydro-cholesterol. Y

2. A process for producing 7-dehydro-cholesterol which comprises dissolving in an organic solvent a carboxylic acid ester or cholesterol, heating said solution in the presence of an oxidizing agent, separating from the reaction mixture the so-produced 'I-hydroxy cholesterol, converting said compound to 7-hydroxy-cholesterol dibenzoate, thermally decomposing said diester to 7-dehydro-cholesterol-benzoate, and saponifying said product to produce 7-dehydrocholesterol.

3. A process for producing '7-dehydro-cholesteroLwhich comprises dissolving cholesterol acetate in glacial acetic acid, adding. thereto lead tetra-acetate, heating the solution to about 60 C. 1or several hours, saponif ying the resulting product and separating therefrom 7-hydroxycholesterol, converting said product to 7-hydroxycholesterol-dizenzoate, thermally decomposing said diester to produce 7-dehydro-cholesterolbenzoate, and saponifying said product to produce 7-dehydrocholesterol.

HANS R. ROSENBERG. 

